Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance
Justin W. Gorski,
Zhuwei Zhang,
J. Robert McCorkle,
Jodi M. DeJohn,
Chi Wang,
Rachel W. Miller,
Holly H. Gallion,
Charles S. Dietrich,
Frederick R. Ueland,
Jill M. Kolesar
Affiliations
Justin W. Gorski
Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0263, USA
Zhuwei Zhang
Department of Cancer Biostatistics, University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0263, USA
J. Robert McCorkle
Department of Pharmacy Practice & Science, University of Kentucky College of Pharmacy, 540 Healthy Kentucky Research Building, 760 Press Avenue, Lexington, KY 40539-0596, USA
Jodi M. DeJohn
University of Kentucky College of Medicine, 800 Rose Street, MN150, Lexington, KY 40536-0298, USA
Chi Wang
Department of Cancer Biostatistics, University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0263, USA
Rachel W. Miller
Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0263, USA
Holly H. Gallion
Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0263, USA
Charles S. Dietrich
Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0263, USA
Frederick R. Ueland
Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0263, USA
Jill M. Kolesar
Department of Pharmacy Practice & Science, University of Kentucky College of Pharmacy, 540 Healthy Kentucky Research Building, 760 Press Avenue, Lexington, KY 40539-0596, USA
The development of patient-derived tumor organoids (TOs) from an epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine. Here, we utilized TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high-grade, serous epithelial ovarian cancer tumor organoid lines from tissue obtained during debulking surgery (two neoadjuvant-carboplatin-exposed and four chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1, and 0.1 µM). Cell viability curves and resultant EC50 values were determined. One organoid line, UK1254, was predicted to be resistant to carboplatin based on its EC50 value (50.2 µM) being above clinically achievable Cmax. UK1254 had a significantly shorter PFS than the rest of the subjects (p = 0.0253) and was treated as a platinum-resistant recurrence. Subsequent gene expression analysis revealed extensively interconnected, differentially expressed pathways related to NF-kB, cellular differentiation (PRDM6 activation), and the linkage of B-cell receptor signaling to the PI3K–Akt signaling pathway (PI3KAP1 activation). This study demonstrates that patient-derived tumor organoids can be developed from patients at the time of primary or interval debulking surgery and may be used to predict clinical platinum sensitivity status or to investigate drivers of carboplatin resistance.
